Dosing & Uses
Dosage Forms & Strengths
tablet
- 40mg
Colorectal Cancer
Indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild type, an anti-EGFR therapy
160 mg (four 40-mg tablets) PO qDay for the first 21 days of each 28-day cycle
Continue treatment until disease progression or unacceptable toxicity
Also see Administration
Gastrointestinal Stromal Tumors
Indicated for the treatment of locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) in patients who have been previously treated with imatinib mesylate and sunitinib
160 mg (four 40-mg tablets) PO qDay for the first 21 days of each 28-day cycle
Continue treatment until disease progression or unacceptable toxicity
Also see Administration
Hepatocellular Carcinoma
Indicated for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib
160 mg (four 40-mg tablets) PO qDay for the first 21 days of each 28-day cycle
Continue treatment until disease progression or unacceptable toxicity
Also see Administration
Dosage Modifications
Interrupt dose
- Grade 2 hand-foot skin reaction (HFSR)/palmar-plantar erythrodysesthesia (PPES) that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR
- Symptomatic Grade 2 hypertension
- Any Grade 3 or 4 adverse reaction
Reduce dose to 120 mg/day
- For the first occurrence of Grade 2 HFSR of any duration
- After recovery of any Grade 3 or 4 adverse reaction except infection
- For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation; only resume if the potential benefit outweighs the risk of hepatotoxicity
Reduce dose to 80 mg/day
- For reoccurrence of Grade 2 HFSR at the 120 mg dose
- After recovery of any Grade 3 or 4 adverse reactions at the 120 mg dose (except hepatotoxicity or infection)
Discontinue permanently
- Failure to tolerate 80 mg dose
- Any occurrence of AST/ALT >20x ULN
- Any occurrence of AST/ALT >3x ULN with concurrent bilirubin >2x ULN
- Reoccurrence of AST/ALT >5x ULN despite dose reduction to 120 mg
- For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks
Renal Impairment
- Mild-to-severe: No dosage adjustment necessary
- Patients on dialysis: Not studied
Hepatic Impairment
- Mild (total bilirubin ≤ULN and AST>ULN, or total bilirubin >ULN to ≤1.5x ULN) or moderate (total bilirubin >1.5 to ≤3x ULN and any AST): No dosage adjustment necessary
- Severe (total bilirubin >3x ULN): Not recommended; not studied
Glioblastoma Multiforme (Orphan)
Orphan designation for glioblastoma multiforme
Orphan sponsor
Bayer HealthCare Pharmaceuticals, Inc; 100 Bayer Boulevard; P.O. Box 915; Whippany, New Jersey 07981
Safety and efficacy not established
Interactions
Interaction Checker
No Results

Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor

Adverse Effects
All grades of severity are listed unless otherwise indicated
>10% (Colorectal Cancer)
Anemia (79%)
Increased AST (65%)
Asthenia (64%)
Proteinuria (60%)
Hypocalcemia (59%)
Hypophosphatemia (57%)
Lymphopenia (54%)
Decreased appetite and food intake (47%)
Increased lipase (46%)
HFSR/PPES (45%)
Hyperbilirubinemia (45%)
Increased ALT (45%)
Diarrhea (43%)
Thrombocytopenia (41%)
Mucositis (33%)
Weight loss (32%)
Infection (31%)
Hypophosphatemia, Grade 3 or 4 (31%)
Hypertension (30%)
Dysphonia (30%)
Hyponatremia (30%)
Pain (29%)
Fever (28%)
Rash (26%)
Hypokalemia (26%)
Increased amylase (26%)
Increased INR (24%)
Hemorrhage (21%)
Nausea (20%)
HFSR/PPES, Grade 3 or 4 (17%)
Asthenia/fatigue, Grade 3 or 4 (15%)
>10% (GIST)
HFSR/PPES (67%)
Pain (60%)
Hypertension (59%)
Proteinuria (59%)
Increased AST (58%)
Hypophosphatemia (55%)
Asthenia (52%)
Diarrhea (47%)
Mucositis (40%)
Dysphonia (39%)
Increased ALT (39%)
Hyperbilirubinemia (33%)
Infection (32%)
Decreased appetite and food intake (31%)
Rash (30%)
Lymphopenia (30%)
Alopecia (24%)
ever (21%)
HFSR/PPES, Grade 3 or 4 (22%)
Hypokalemia (21%)
Nausea (20%)
Hypophosphatemia, Grade 3 or 4 (20%)
Hypothyroidism (18%)
Vomiting (17%)
Hypocalcemia (17%)
Headache (16%)
Neutropenia (16%)
Weight loss (14%)
Increased lipase (14%)
Muscle spasms (14%)
Thrombocytopenia (13%)
Hemorrhage (11%)
>10% (HCC)
Increased AST (93%)
Hyperbilirubinemia (78%)
Hypophosphatemia (70%)
Increased ALT (70%)
Lymphopenia (68%)
Thrombocytopenia (63%)
Pain (55%)
Proteinuria (51%)
HFSR/PPES (51%)
Increased INR (44%)
Asthenia/fatigue (42%)
Diarrhea (41%)
Increased lipase (41%)
Hypophosphatemia, Grade 3 or 4 (31%)
Hypertension (31%)
Infection (31%)
Hypokalemia (31%)
Decreased appetite and food intake (31%)
Hypocalcemia (23%)
Increased amylase (23%)
Fever (20%)
Hypothyroidism (18%)
Hemorrhage (18%)
Dysphonia (18%)
Nausea (17%)
Hypocalcemia (17%)
Proteinuria, Grade 3 or 4 (17%)
Headache (16%)
Hypertension, Grade 3 or 4 (15%)
Neutropenia (14%)
Mucositis (13%)
Vomiting (13%)
Weight loss (13%)
Hyperbilirubinemia, Grade 3 or 4 (13%)
HFSR/PPES, Grade 3 or 4 (12%)
Increased lipase, Grade 3 or 4 (11%)
1-10% (Colorectal Cancer)
Headache (10%)
Hyperbilirubinemia, Grade 3 or 4 (10%)
Pain, Grade 3 or 4 (9%)
Infection, Grade 3 or 4 (9%)
Increased lipase, Grade 3 or 4 (9%)
Lymphopenia, Grade 3 or 4 (9%)
Hypertension, Grade 3 or 4 (8%)
Diarrhea, Grade 3 or 4 (8%)
Hypokalemia, Grade 3 or 4 (7%)
Musculoskeletal stiffness (6%)
Rash, Grade 3 or 4 (6%)
Decreased appetite and food intake, Grade 3 or 4 (5%)
Anemia, Grade 3 or 4 (5%)
Increased AST/ALT, Grade 3 or 4 (6%)
Mucositis, Grade 3 or 4 (4%)
Hypokalemia, Grade 3 or 4 (4%)
Neutropenia (3%)
Tremor (2%)
Hemorrhage, Grade 3 or 4 (2%)
Fever, Grade 3 or 4 (2%)
Proteinuria, Grade 3 or 4 (2%)
Increased amylase, Grade 3 or 4 (2%)
Neutropenia, Grade 3 or 4 (1%)
Hypocalcemia, Grade 3 or 4 (1%)
1-10% (GIST)
Lymphopenia, Grade 3 or 4 (8%)
Pain, Grade 3 or 4 (8%)
Diarrhea, Grade 3 or 4 (8%)
Rash, Grade 3 or 4 (8%)
Infection, Grade 3 or 4 (5%)
Asthenia/fatigue, Grade 3 or 4 (4%)
Hemorrhage, Grade 3 or 4 (4%)
Increased AST/ALT, Grade 3 or 4 (3-4%)
Hyperbilirubinemia, Grade 3 or 4 (3%)
Proteinuria, Grade 3 or 4 (3%)
Hypokalemia, Grade 3 or 4 (3%)
Neutropenia, Grade 3 or 4 (2%)
Mucositis, Grade 3 or 4 (2%)
Nausea, Grade 3 or 4 (2%)
Hypocalcemia, Grade 3 or 4 (2%)
Thrombocytopenia, Grade 3 or 4 (1%)
1-10% (HCC)
Muscle spasms (10%)
Asthenia/fatigue, Grade 3 or 4 (10%)
Infection, Grade 3 or 4 (8%)
Increased ALT, Grade 3 or 4 (6%)
Hemorrhage, Grade 3 or 4 (5%)
Thrombocytopenia, Grade 3 or 4 (5%)
Neutropenia, Grade 3 or 4 (4%)
Diarrhea, Grade 3 or 4 (3%)
Diarrhea, Grade 3 or 4 (3%)
Decreased appetite or food intake (3%)
Weight loss (2%)
Mucositis, Grade 3 or 4 (1%)
<1%
GIST
- Decreased appetite and food intake, Grade 3 or 4
- Vomiting, Grade 3 or 4
HCC
- Nausea
- Vomiting
- Increased INR
Colorectal cancer
- Headache, Grade 3 or 4
Postmarketing Reports
Hypersensitivity reactions
Nephrotic syndrome
Cardiac failure
Arterial (including aortic) aneurysms, dissections, and rupture
Warnings
Black Box Warnings
Hepatotoxicity
- Severe and sometimes fatal hepatotoxicity observed in clinical trials
- Monitor hepatic function prior to and during treatment
- Interrupt and then reduce or discontinue for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence
- Also see Dosage Modifications and Cautions
Contraindications
None
Cautions
Also see Dosage Modifications
May cause severe drug-induced liver injury with fatal outcome (see Black Box Warnings); obtain liver function tests (ALT, AST, and bilirubin) before initiation of therapy and monitor at least every 2 weeks during first 2 months of treatment; thereafter, monitor monthly or more frequently as clinically indicated; monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline; temporarily hold and then reduce or permanently discontinue therapy depending on severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis
Increases risk for hemorrhage; discontinue therapy for severe or life-threatening hemorrhage
Increased risk of infections reported; most common infections include urinary tract infections, nasopharyngitis, mucocutaneous and systemic fungal infections and pneumonia
Increases risk for HFSR/PPES and rash; a higher incidence of HFSR reported in Asian patients; interrupt and then reduce or discontinue regorafenib depending on severity and persistence of dermatologic toxicity
Hypertension may occur, typically during the first treatment cycle; do not initiate therapy unless blood pressure is adequately controlled; monitor blood pressure weekly for first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated; temporarily or permanently withhold therapy for severe or uncontrolled hypertension
Myocardial ischemia and infarction observed in clinical trials; withhold regorafenib for new or acute cardiac ischemia/infarction and resume only after resolution of acute ischemic events
One case report of reversible posterior leukoencephalopathy syndrome (RPLS) reported (1 of 1100 treated patients); discontinue therapy if RPLS occurs
Discontinue therapy if gastrointestinal perforation or fistula occur
May impair wound healing (class effect of VEGFR inhibitors); complications can occur in patients who receive drugs that inhibit the VEGF signaling pathway; discontinue at least 2 weeks before scheduled surgery; do not administer for at least 2 weeks following major surgery and until adequate wound healing; safety of resumption of drug after resolution of wound healing complications not established; discontinue therapy in patients with wound dehiscence
Embryo-fetal toxicity likely if taken while pregnant (see Pregnancy & Lactation)
Drug interactions overview
-
Strong CYP3A4 inhibitors
- Coadministration with strong CYP3A4 inhibitors increases regorafenib plasma concentrations, decreased active metabolite (M-2 and M-5) plasma concentrations, and may increase toxicity
- Avoid concomitant use of regorafenib with strong CYP3A4 inhibitors (eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole)
-
Breast cancer resistance protein (BCRP) substrates
- Coadministration with a BCRP substrate increases the BCRP substrate plasma concentrations
- Closely monitor for signs and symptoms of exposure-related toxicity of the BCRP substrate (eg, methotrexate, fluvastatin, atorvastatin)
- Consult the concomitant BCRP substrate product information when considering administration of regorafenib
-
UGT substrates
- Regorafenib competitively inhibits UGT1A9 and UGT1A1 substrates
Pregnancy & Lactation
Pregnancy
Based on animal studies and mechanism of action, fetal harm may occur when administered to a pregnant woman
There are no available data on use in pregnant women
Advise pregnant women of the potential hazard to a fetus
Animal data
- Administration of regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations
Contraception
- Females: Use effective contraception during treatment and for 2 months following the final dose
- Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 months following final dose
Infertility
- There are no data on the effect on human fertility
- Results from animal studies indicate that regorafenib can impair male and female fertility
Lactation
There are no data on the presence of regorafenib or its metabolites in human milk, the effects of regorafenib on the breastfed infant, or on milk production In rats, regorafenib and its metabolites are excreted in milk
Because of the potential for serious adverse reactions in breastfed infants from regorafenib, do not breastfeed during treatment and for 2 weeks after the final dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Tyrosine kinase inhibitor; shown to inhibit activity of membrane-bound and intracellular kinases involved in normal cellular functions and in pathological processes (eg, oncogenesis, tumor angiogenesis) RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl
Absorption
Bioavailability: 69-83% (with low fat meal)
Peak Plasma Time: 4 hr
Peak Plasma Concentration: 2.5 mcg/mL (single dose); 3.9 mcg/mL (steady-state)
AUC: 70.4 mcg•h/mL (single dose); 58.3 mcg•h/mL (steady-state)
Distribution
Protein Bound: 99.5% (regorafenib); 99.8% (M-2 active metabolite); 99.95% (M-5 active metabolite)
Undergoes enterohepatic circulation with multiple plasma concentration peaks observed during 24-hr interval
Metabolism
Metabolized by CYP3A4 and UGT1A9
Metabolites (active): M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in vitro pharmacological activity and steady-state concentrations as regorafenib
Elimination
Half-life: 28 hr (regorafenib); 25 hr (M-2 active metabolite); 51 hr (M-5 active metabolite)
Excretion: 71% feces; 19% urine (within 12 days of single dose)
Administration
Oral Administration
Administer orally same time each day
Swallow table whole with water, do not split, chew, or crush
Take after a low-fat meal that contains <600 calories and <30% fat
Do not take 2 doses on the same day to make up for a missed dose from the previous day
Storage
Tablets: Store at 25°C (77°F); excursions are permitted from 15-30°C (59-86°F)
Store tablets in the original bottle and do not remove the desiccant
Keep the bottle tightly closed after first opening
Discard any unused tablets 7 weeks after opening the bottle; dispose of unused tablets in accordance with local requirements
Images
Patient Handout
Formulary
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Adding plans allows you to:
- View the formulary and any restrictions for each plan.
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- Compare formulary status to other drugs in the same class.
- Access your plan list on any device – mobile or desktop.